Summary: Neuromyelitis optica (NMO) is a rare but devastating inflammatory disorder of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord. NMO was initially characterized as a subset of multiple sclerosis (MS), but is now considered a distinct disease. It has been shown that both type I interferon (IFN-I) and T helper 17 (TH17) cells play a critical role in the pathology of NMO, however it is unclear how IFN-I and TH17 cooperate to drive disease pathology. Our preliminary data now show that IFN-I gene signatures are elevated in blood from NMO and are highly correlated with TH17 signatures. Furthermore, our studies using mice with TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE) supports the hypothesis that IFN-I fuels TH17-mediated disease by stimulating antigen presenting cells to produce IL-6 which in turn drives the production of GM-CSF and other inflammatory cytokines. For this grant application, we propose to use NMO patient samples and TH17-EAE to study how TH17 and IFN-I cooperate in driving neuro-inflammation in human disease and in an in vivo animal model. In AIM 1, we will use RNA-sequencing to identify the discrete cell types that harbor the IFN-I signature in NMO patients and discover novel genes that could regulate IFN-I and TH17 pathways. In Aim 2, we will perform in vitro culture experiments to determine how IFN-I affects T helper cell differentiation in NMO patients compared to healthy controls. In Aim 3, we will use the TH17-EAE model to understand the mechanisms by which IFN-I exacerbates TH17-induced neuro-autoimmune disease. The combination of research on human subject and the mechanistic animal experiments outlined in this proposal have the potential to give deep insight into pathological processes that underlie NMO and other autoimmune diseases with IFN-I and TH17 signatures.